4-Phenylpiperidine compounds for treating depression

ABSTRACT

The invention relates to a compound, and pharmaceutically acceptable salts, having the formula I: ##STR1## wherein: R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C 1-4  alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl, 
     R 1  represents hydrogen, trifluoro (C 1-4 ) alkyl, alkyl or alkynyl, 
     X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy, 
     R 2  represents: 
     a C1-C10 alkyl group, 
     a phenyl group optionally substituted by one or more of the following groups: 
     a C1-C10 alkyl group, 
     a halogen group, 
     a nitro group, 
     hydroxy group, 
     and/or an alkoxy group.

The present invention relates to a group of tri-substituted, 4-phenylpiperidines, to a process for preparing such compounds, to a medicament comprising such compounds, and to the use of such compounds for the manufacture of a medicament.

The compound paroxetine, trans-4-(4'-fluorophenyl)-3-(3',4'-methylene dioxyphenoxymethyl) piperidine having the formula below: ##STR2## is known and has been used in medicaments for treating, amongst other ailments, depression.

Paroxetine has been used as a therapeutic agent in the form of a salt with pharmaceutically acceptable acids. The first clinical trials were conducted with the acetate salt.

A known useful salt of paroxetine is the hydrochloride. This salt is considered to be the active substance in several marketed pharmaceutical products, e.g. Paxil or Seroxat. A number of forms of paroxetine hydrochloride have been described:

the anhydrous form in several crystalline modifications (PCT Appl. WO 96/24595);

the hydrated form--a hemihydrate (EP 223403) and in the solvated forms.

The comparison of behaviour between anhydrous and hydrated form of paroxetine hydrochloride is described in the Intl. Journal of Pharmaceutics 42, 135-143 (1988).

EP 223403 discloses paroxetine hydrochloride hemihydrate and pharmaceutical compositions based thereon.

Most of these known salts of paroxetine have unsuitable physico-chemical characteristics for ensuring safe and efficient handling during production thereof and formulation into final forms, since they are unstable (acetate, maleate) and possess undesirable hygroscopicity.

Furthermore their formation by crystallization from both aqueous or non-aqueous solvents is generally low-yielded and troublesome as they usually contain an undefined and unpredicted amount of bound solvent which is difficult to remove.

The crystalline paroxetine hydrochloride hemihydrate approaches these problems, but as stated in WO 95/16448, its limited photostability causes undesired colouration during classical wet tabletting procedure.

Moreover, crystalline paroxetine hydrochloride hemihydrate exhibits only limited solubility in water.

It has been generally suggested that where the aqueous solubility is low, for example less than 3 mg/ml, the dissolution rate at in vivo administration could be rate-limiting in the absorption process. The aqueous solubility of the paroxetine hemihydrate at room temperature exceeds this threshold by a relatively small margin.

An object of the present invention is to provide a compound with improved characteristics.

According to a first aspect, the present invention comprises a compound, and pharmaceutically acceptable salts, having the formula I: ##STR3## R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C₁₋₄ alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl,

R¹ represents hydrogen, trifluoro (C₁₋₄) alkyl, alkyl or alkynyl,

X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy,

R² represents:

a C1-C10 alkyl group,

a phenyl group optionally substituted by one or more of the following groups:

a C1-C10 alkyl group,

a halogen group,

a nitro group,

hydroxy group,

and/or an alkoxy group.

The inventors have found that these compounds exhibit good stability and very high solubility. This yields the advantage that high concentrations of the compound are obtainable in small volumes.

The R group is preferably the 3,4 methylenedioxyphenyl group of the formula: ##STR4##

The X group is preferably a fluorine group attached to position 4 in the phenyl ring.

The R² group preferably represents a C1-C4 alkyl group, and most preferably represents a C1-C2 alkyl group in order to provide an optimum solubility.

The compounds can have a solubility at about 20° C. of at least about 10 mg/ml water, preferably having a solubility in water of at least 100, for example 500 and most preferably of at least 1000 mg/ml water.

According to a second aspect of the present invention, there is provided a process for preparing a compound as above, comprising the steps of mixing together a 4 phenylpiperidine compound, a salt and/or a base thereof having the formula II: ##STR5## wherein: R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C₁₋₄ alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl,

R₁ represents hydrogen, trifluoro (C₁₋₄) alkyl, alkyl or alkynyl,

X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy,

with a sulfonic acid of the general formula R₂ -SO₃ H, wherein R₂ represents:

a C1-C10 alkyl group,

a phenyl group optionally substituted by one or more of he following groups:

a C1-C10 alkyl group,

a halogen group,

a nitro group,

a hydroxy group, and/or

an alkoxy group,

to form a solution, followed by separating the compound formed from this solution.

The compounds of the invention can be prepared from the free base of the 4 phenylpiperidine, having the formula II, this preferably being paroxetine, by treatment with a sulfonic acid as defined above in a suitable solvent to form a solution of the desired acid addition salt, whereafter this is precipitated out of the solution.

The equation for paroxetine free base and sulfonic acids is as follows: ##STR6##

The forming of a solution may preferably proceed at temperatures from about 0° C. to the boiling point of the solvent.

Optionally, the solution may be purified by treatment of activated charcoal, silica gel, kieselguhr or other suitable materials.

Alternatively, the solution of a salt of the invention can be formed by dissolution of a salt of 4 phenyl piperidine having the formula II with an organic sulfonic acid.

For example the compounds of the invention may be prepared from a paroxetine C1-C5 carboxylate, such as the acetate, by addition of corresponding organic sulfonic acid to the solution of the said carboxylate, as follows: ##STR7##

According to a third aspect of the present invention, there is provided a compound obtainable by this process.

According to a fourth aspect of the present invention there is provided the above compound for use as a medicament and, according to a fifth aspect, a medicament comprising this compound, and to the use thereof for treating depressions, obsessive compulsive disorders, panic disorders, bulimia, anorexia, pain, obesity, senile demential, migraine, anorexia, social phobia, depressions arising from pre-menstrual tension.

According to a sixth aspect of the present invention, there is provided the use of a compound of the invention as a reagent in further syntheses. More specifically, the compounds of the present invention can be used as a start reagent for forming further acid addition salts, for example for providing further paroxetine acid addition salts, by reacting with a suitable regent, i.e. with a corresponding acid. For example, the formation of paroxetine maleate according to the present invention proceeds by the following equation: ##STR8## and the formation of paroxetine acetate proceeds as follows: ##STR9##

This is an advantageous route, since by using the substantially pure sulfonic acid salts according to the present invention as a start reagent, the preparation of a further salt, as above, results in this further salt having a high purity. The inventors have shown that such salts have a surprisingly high purity.

Similarly, the compounds of the present invention can react with a base, such as an inorganic and/or an organic base, to form (liberate) free bases of the corresponding compounds. As exemplified on paroxetine, the reaction proceeds according to the equation: ##STR10##

The free bases liberated from the compounds of the present invention have surprisingly higher purity than if prepared by known methods which is especially important in case of their use for production of pharmaceuticals.

Accordingly, the new compounds of the first aspect of the invention can also form hydrates and/or solvates by a contact with a corresponding reaction partner, i.e. with water and/or with a solvent. Examples of such further salts, hydrates and solvates, for example these of paroxetine, are the:

    ______________________________________     hydrochloride  oxalate      dihydrate     hydrobromide   succinate    trihydrate     hydroiodide    tartrate     hexahydrate     acetate        citrate      methanolate     propionate     embonate     ethanolate     maleate        hemihydrate     fumarate       hydrate     ______________________________________

The inventors have shown that such salts have a surprisingly high purity.

Examples of bases which can be employed in the preparation of the free bases are: sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, triethylamine, pyridine and such like.

Since the compounds according to the present invention exhibit high solubility, they can be dosed, for example injected, in a high concentration, low volume solution, this method of dosing being particularly advantageous with certain patients, such as manic depressives and such like, i.e. patients who are unable or unwilling to swallow medicine.

The compounds of the present invention can be formulated into various types of pharmaceutical compositions for treatment of humans and animals. Pharmaceutical compositions according to the present invention comprise a compound of the invention alone or together with a pharmaceutically acceptable carrier or diluent. The preferred formulations are those for oral administration (tablets, capsules) but formulations for parenteral or topical administration are also within the scope of the invention. The high water solubility of the compounds of the invention enables high dissolution rates in solid dosage forms based on the compounds of the invention to be obtained, during the in vitro release as well as good bioavailability after peroral application in vivo.

The tablets containing compounds of the present invention can be prepared both by tabletting procedure in which water is present (e.g. aqueous granulation) as well as by tabletting processing it which water is absent (direct compression, dry granulation) and may be coated by any suitable means of coating.

The present invention will now be further elucidated by way of the following examples and results.

EXPERIMENTAL

A seeding crystal of paroxetine methane sulfonate was made as follows:

2.7 g (8.2 mmol) of paroxetine was dissolved in

15 ml of hot ethanol.

1.0 g (10.4 mmol) of methanesulfonic acid in

15 ml of ethanol was added and the mixture was cooled to room temperature. When the mixture had reached room temperature the mixture was put in the freezer at -20° C. overnight. No crystal line compound was obtained. The mixture was evaporated to dryness leaving an oil. After 1 month at room temperature a waxy solid was obtained. Part of this solid was taken apart and the rest was dissolved in

10 ml of EtOAc. The waxy crystals were added and the mixture was put in the freezer at -20° C. overnight. A white crystalline product was precipitated. After filtration and drying in a vacuumoven

2.5 g (5.9 mmol) of paroxetine methane sulfonate was obtained.

Yield 72%

This seeding crystal was subsequently used in following examples 1 and 3.

EXAMPLES Example 1 Paroxetine methane sulfonate from paroxetine

To a solution of 43.5 g (132 mmol) of paroxetine, prepared by the procedure disclosed in U.S. Pat. No. 4,007,196,

12.7 g (132 mmol) of methane sulfonic acid was added to

150 ml of boiling ethyl acetate. The mixture was left at room temperature for 2 hours. Subsequently the mixture was placed overnight at -20° C., with a seeding crystal. The obtained solid was filtered off and washed with

50 ml of ether. The obtained white solid was dried overnight in a vacuumoven.

47.1 g (111 mmol) of product

Yield 99.5%

Analytical characterization of the compound obtained is shown in Table 1. The purity of the compound obtained was 98% (HPLC).

Example 2 Paroxetine Benzene Sulfonate From Paroxetine

3.8 g (11.5 mmol) of paroxetine was dissolved in

10 ml of hot ethylacetate.

1.82 g (11.5 mmol) of anhydrous benzenesulfonic acid was added. The mixture was left at room temperature for 2 h. The mixture was evaporated to dryness and dissolved in dichloromethane, and evaporated again to dryness leaving an oil. This oil was solidified through high vacuum (0.1 mmHg) evaporation leaving

5.0 g (1.3 mmol) of an off white solid. To this solid was added

5 ml of acetone and the suspension was stirred for 5 minutes during which a white suspension was obtained. The solid was filtered off and dried under vacuum.

4.8 g (9.9 mmol) of product was obtained.

Yield 85%.

Analytical characterization of the compound obtained is shown in Table 1. The purity of the compound obtained was 99.4% (HPLC).

Example 3 Paroxetine p-toluene Sulfonate From Paroxetine

5.0 g (15 mmol) of paroxetine was dissolved in

25 ml of hot ethylacetate.

2.9 g (15 mmol) of p-toluenesulfonic acid was added. The mixture was left at room temperature for 2 h and subsequently put in the freezer, with a seeding crystal, for 14 h. The solid was filtered off and washed once with

10 ml of n-hexane. The obtained white solid was dried overnight in a vacuumoven.

4.8 g (10 mmol) of a white solid was obtained.

Yield 67%

Analytical characterization of the compound obtained is shown in Table 1. The purity of the compound obtained was 99.4% (HPLC).

Example 4 Paroxetine p-chlorobenzene Sulfonate From Paroxetine

1.1 g (3.3 mmol) of paroxetine was dissolved in

3 ml of hot ethylacetate.

0.76 g (3.3 mmol) of 90% p-chlorobenzenesulfonic acid was added. The mixture was left at room temperature for 1 h and washed with

5 ml of water. The organic layer was dried with Na₂ SO₄, filtered and evaporated to dryness leaving

1.5 g (2.9 mmol) of an off white solid.

Yield 88%

Analytical characterization of the compound obtained is shown in Table 1. The purity of the compound obtained was 99.4% (HPLC).

Example 5 Paroxetine Maleate From Paroxetine Methane Sulfonate

1.0 g (2.4 mmol) of paroxetine methane sulfonate in

5 ml of hot water. To this solution was added

0.32 g (2.8 mmol) of maleic acid. The mixture was placed at 4° C. overnight after which a solid with a yellow oil was precipitated on the bottom of the flask. The solid/oil was filtered off and washed 3 times with

10 ml of ether and dried in a vacuumoven.

0.8 g (2.0 mmol) off white crystals were obtained

Yield 85%

The purity of the compound obtained was 99.5% (HPLC).

Example 6 Paroxetine Acetate From Paroxetine Methane Sulfonate

1.0 g (2.4 mmol) of paroxetine methane sulfonate in

5 ml of hot iso-propanol. To this solution was added

0.2 g (3.2 mmol) of acetic acid. The mixture was placed at 4° C. overnight after which a solid was precipitated. The solid was filtered off and washed 3 times with

10 ml of ether and dried in a vacuumoven.

0.5 g (1.3 mmol) off white crystals were obtained

Yield 54%

The purity of the compound obtained was 99.5% (HPLC).

Example 7 Paroxetine free base from paroxetine methane sulfonate

10.0 g (24.0 mmol) of paroxetine methane sulfonate in

150 ml of water and

200 ml of ethyl acetate. To this was added

12.4 g (31 mmol) of an aqueous 10 wt % NaOH solution and the suspension was stirred for 15 minutes. The layers were separated and the aqueous layer was extracted once with

50 ml of ethyl acetate. The combined organic layers are washed once with

100 ml of water and dried over Na₂ SO₄. The Na₂ SO₄ was filtered off and washed once with

50 ml of ethyl acetate. The ethyl acetate was evaporated off, leaving

7.5 g (22.8 mmol) of an oily product.

Yield 95%

The purity of the compound obtained was 99.5% (HPLC).

A number of the compounds obtained were analysed, the results being shown in tables 1-5 below:

                  TABLE 1     ______________________________________     Characterization of salts of paroxetine with cortain organic acids     R-SO.sub.3 H     ______________________________________     R = CH.sub.3 (paroxetine methane sulfonate):     m.p.: 142°-144° C.     DSC curve (closed pan, 10° C./min): onset 145.8° C. 79.0     l/g     LR spectrum ( KBr, in cm.sup.-1); 531, 546, 777, 838, 931, 962, 1038,     1100, 1169, 1208, 1469, 1500, 1515, 1615, 2577, 2869, 2900, 3023.     1H-NMR (ppm): 1.99 (br d, H.sub.5eg, 1H): 2.27 (ddd, H.sub.5ax, 1H);     2.48-2.65 (m, H.sub.3, 1H); 2.82-2.92 (m, H.sub.4, CH.sub.3, 4H);     2.95-3.20     (m, H.sub.2ax, II.sub.6ax, 2H); 3.47 (dd, H.sub.7, 1H); 3.58-3.74     (m,H.sub.2eg, H.sub.6eg, H.sub.7 3H): 5.88 (x, II.sub.7" 2H); 6.10 (dd,     H.sub.6", 1H); 6.33     (d, H.sub.2", 1H): 6.61 (d, H.sub.5", 1H); 7.09 (dd, H.sub.3', H.sub.5',     2H); 7.22 (dd H.sub.2',     II.sub.6', 2H); 8.85 (br d, NH.sub.eq, 1H); 9.11 (br d, NH.sub.ax, 1H).     13C-NMR (ppm): 30.0 (s, C.sub.5); 39.3 (s, C.sub.3); 39.5 (s, C.sub.4);     41.7 (s, SC);     44.6 (s, C.sub.6); 46.8 (s, C.sub.2); 67.4 (s, C.sub.7); 97.8 (s,     C.sub.2",); 101.2     (s, C.sub.7"); 105.4 (s, C.sub.6"); 107.8 (s, C.sub.5"); 115.8 (d,     C.sub.3", C.sub.5); 128.4     (s, C.sub.6', C.sub.2); 137.1 (s, C.sub.4"); 142.0 (s, C.sub.1); 148.2     (s, C.sub.3); 153.7 (s, C.sub.1");     161.9 (d, C.sub.4,).     R= C.sub.6 H.sub.5 (paroxetine benzene sulfonate):     m.p.: 55°-60° C.     IR spectrum (KBr, in cm.sup..sup.31 1): 530, 564, 614, 689, 728, 764,     828, 929, 993,     1007, 1029, 1121, 1179, 1229, 1443, 1471, 1486, 1514, 1600, 1628, 2557,     2842, 3029.     1H-NMR (ppm): 1.90 (br d, H.sub.5eg, 1H); 2.10-2.28 (m, H.sub.5ax, 1H);     2.38-2.52 (m, H.sub.3, 1H); 2.82 (ddd, H.sub.4, 1H); 3.02-3.18 (m,     H.sub.2ax,     H.sub.6ax, 2H); 3.37 (dd, H.sub.7, 1H); 3.48 (d, H.sub.7, 1H); 3.60-3.82     (m, H.sub.2eg,     H.sub.6eg, 2H); 5.87 (s, H.sub.7", 2H); 6.06 (dd, H.sub.6", 1H); 6.29 (d,     H.sub.2", 1H); 6.60     (d, H.sub.5", 1H); 6.90 (dd, II.sub.3, H.sub.5, 2H); 7.04 (dd, H.sub.2,     H.sub.6, 2H); 7.40     (d, ArH, 3H); 7.94 (d, SArH, 2H); 8.81 (br d, NH.sub.eg, 1H); 9.04 (br     d,     NH.sub.ax, 1H).     13C-NMR (ppm): 29.9 (s, C.sub.5); 39.2 (s, C.sub.3); 41.5 (s, C.sub.4);     44.8 (s, C.sub.6);     47.0 (s, C.sub.2); 67.3 (s, C.sub.7); 97.9 (s, C.sub.2"); 101.2 (s,     C.sub.7"); 105.5 (s, C.sub.6", )     107.8 (s, C.sub.5",); 115.7 (d, C.sub.3', C.sub.5,); 125.9 (s, C.sub.b);     128.8 (s, C.sub.d); 128.8     (s, C.sub.6, C.sub.2,); 130.6 (s, C.sub.ax); 137.1 (s, C.sub.4"); 141.9     (s, C.sub.1); 144.1 (s, C.sub.3);     148.2 (s, C.sub.3",); 153.7 (s, C.sub.1",); 161.8 (s, C.sub.4,).     R = p-CH.sub.3 C.sub.6 H.sub.4 (paroxetine p-toluene sulfonate):     m.p.: 148°-150° C.     DSC curve (closed pan, 10° C./min): onset 151.6° C., 71.6     I/g.     IR spectrum (KBr, in cm.sup.-1); 529, 557, 673, 771, 800, 814, 921, 936,     1000, 1029, 1100, 1157, 1136, 1229, 1471, 1486, 1507, 1600, 2557, 2829,     3029.     1H-NMR (ppm): 1.89 (br d, H.sub.5eg, 1H); 2.10-2.50 (m, H.sub.5ax,     H.sub.3, CH.sub.3,     5H); 2.82 (ddd, H.sub.4 1H); 2.97-3.18 (m, H.sub.2ax, H.sub.6ax, 2H);     3.36 (dd,H.sub.7 1H);     3.48 (dd, H.sub.7, 1H); 3.52-3.77 (m, H.sub.2eg, H.sub.6eg, 2H); 5.87 (s,     H.sub.7", 2H); 6.06     (dd, H.sub.6", 1H); 6.28 (d, H.sub.2", 1H); 6.59 (d, H.sub.5", 1H); 6.90     (dd, H.sub.3',     H.sub.5', 2H); 7.05 (dd, H.sub.2', H.sub.6', 2H); 7.24 (d, CH, ArH, 2H);     7.83     (d, SArH, 2H); 8.91 (br d, NH.sub.eg, 1H); 9.17 (br d, NH.sub.ax, 1H).     13C-NMR (ppm): 21.3 (s, C.sub.6); 29.9 (s, C.sub.5); 39.2 (s, C.sub.3);     41.5 (s, C.sub.4);     44.7 (s, C.sub.6); 46.9 (s, C.sub.2); 67.3 (s, C.sub.7); 97.8 (s,     C.sub.2",); 101.1 (s, C.sub.7",);     105.5 (s, C.sub.6",); 107.8 (s, C.sub.5",); 115.6 (d, C.sub.3, C.sub.5,);     125.8 (s, C.sub.b); 129.0     (s, C.sub.6, C.sub.2,); 129.1 (s, C.sub.6); 137.2 (s, C.sub.4" u); 140.8     (s, C.sub.d); 141.5 (s, C.sub.a);     141.9 (s, C.sub.1); 148.2 (s, C.sub.3",); 153.8 (s, C.sub.1",); 161.8 (d,     C.sub.4,).     R = p-ClC.sub.6 H.sub.4 (paroxetine p-chlorobenzene sulfonate):     m.p.: 75°-80° C.     LR spectrum (KBr, in cm.sup.-1): 486, 557, 643, 736, 821, 1000, 1029,     1086,     1114, 1186, 1229, 1471, 1486, 1514, 1600, 1657, 2857, 3029.     1H-NMR (ppm): 1.91 (br d, H.sub.5eg, 1H); 2.15 (ddd, II.sub.5ax, 1H);     2.37-2.52     (m, H.sub.3, 1H); 2.81 (ddd, H4, 1H); 2.93-3.21 (m, H.sub.2ax, H.sub.6ax,     2H); 3.37     (dd, H.sub.7, 1H): 3.49 (d, H.sub.7, 1H), 3.61-3.81 (m, H.sub.2eg,     H.sub.6eg, 2H); 5.88     (s, H.sub.7", 2H); 6.05 (dd, H.sub.6", 1H); 6.27 (d, H.sub.2", 1H); 6.59     (d, H.sub.5", 1H); 6.91     (dd, H.sub.3, H.sub.5, 2H); 7.03 (dd, H.sub.2, H.sub.6, 2H); 7.39 (d,     ClArH, 2H); 7.86     (d, SArH, 2H); 8.78 (br d, NH.sub.eg, 1H); 9.02 (br d, NH.sub.ax, 1H).     13C-NMR (ppm): 30.0 (s, C.sub.5); 39.3 (s, C.sub.3); 41.5 (s, C.sub.4);     44.9 (s, C.sub.6);     47.1 (s, C.sub.2); 67.3 (s, C.sub.7,); 97.9 (s, C.sub.2",); 101.2 (s,     C.sub.7",); 105.5 (s, C.sub.6",);     107.9 (s, C.sub.5",); 115.8 (d, C.sub.3, C.sub.5,); 127.6 (s, C.sub.b);     128.8 (s, C.sub.6, C.sub.2,);     132.0 (s, C.sub.d); 137.0 (s, C.sub.6); 137.2 (s, C.sub.4",); 141.8 (s,     C.sub.1,); 142.0 (s,     C.sub.6,); 148.2 (s, C.sub.3",); 153.6 (s, C.sub.1",); 161.8 (d,     C.sub.4,).     ______________________________________

The compounds of the invention are crystalline, with defined melting points, DSC curves and IR spectra. It cannot be excluded that, under different conditions of their formation and under specific conditions, they could exist also in other crystalline or polymorph modifications which may differ from those as described herein. The compounds of the invention are also generally very stable and non-hygroscopic.

It should be understood that the present invention comprising acid addition salts with organic sulfonic acids are substantially free of the bound organic solvent. Preferably, the amount of bound organic solvent should be less than 2.0% (w/w) as calculated on the anhydrous basis. They nevertheless may contain crystallization water and also unbound water, that is to say water which is other than water of crystallization.

In the following tables 2 and 3, examples of results of hygroscopicity tests and stability tests (in comparison with known salts of paroxetine) are presented.

                  TABLE 2     ______________________________________     Hygroscopicity of certain salts of paroxetine (40° C., 75% rel.     hum).     water content (in %) at                       t = 0     1 = 4 weeks     methane sulfonate 0.35      +0.04     p-toluene sulfonate                       0.70      <0.02     hydrochloride     --        +2.5     ______________________________________

                  TABLE 3     ______________________________________     Solubility of paroxetine salts in water (in mg/ml)                       20° C.                             50° C.     ______________________________________     methane sulfonate   >1000   1300     p-toluene sulfonate >1000   >1000     hydrochloride hemidhydrate                         4.9     12.6     hydrochloride anhydrate                         8.2     24.2     ______________________________________

                  TABLE 4     ______________________________________     Stability of paroxetine salts by HPLC (total amount of degradation in     %).                 degradation                 20° C.                             80° C.     ______________________________________     methane sulfonate                   not observed  <0.2%, 3 months     p-toluene sulfonate                   not observed  <0.2%, 3 months     maleate       0.2%, 12 months                                 >50%, 5 days     ______________________________________

                  TABLE 5     ______________________________________     Solubility of slats of paroxetine in nonaqueous solvents (in mg/ml)                 methane sulfonate                            p-toluene sulfonate     ______________________________________     Ethanol  20° C.                       36           50              78° C.                       250          >500     2-Propanol              20° C.                       7            14              82° C.                       330          >500     Acetone  20° C.                       5            16              56° C.                       37           125     Ethyl acetate              20° C.                       2            22              77° C.                       25           >500     n-Hexane 20° C.                       <0.05        <0.05              69° C.                       0.05         <0.05     ______________________________________

Examples of analytical data of the paroxetine salts and the free base prepared in Examples 5 to 7 are given in Table 6.

                  TABLE 6     ______________________________________     Characterization of salts/free base of praoxetine     ______________________________________     paroxetine maleate:     m.p.: 128-130° C.     1H-NMR (ppm); 1.65-2.00 (m, H.sub.5eg, 2H); 2.00-2.50 (m, H.sub.3, 1H);     2.55-3.15 (m, H.sub.2ax, H.sub.6ax, H.sub.4, 3H); 3.15-3.75 (m,     H.sub.2eg,     H.sub.6eg, H.sub.7 3H); 5.67 (s, H.sub.7, 2H); 5.97 (s, H.sub.a, 1H);     6.12     (dd, H.sub.6", 1H); 6.42 (d, H.sub.2", 1H) 6.67 (d, H.sub.5", 1H);     6.95-7.35     (m, H.sub.2', H.sub.3', H.sub.5', H.sub.6', 4H).     paroxetine acetate:     m.p.; 123-125° C.     1H-NMR (ppm); 1.70-2.00 (m, H.sub.5eg, H.sub.5ax, 2H); 1.97 (s, H.sub.a,     3H);     2.05-2.50 (m, H.sub.3, 1H); 2.50-3.00 (m, H.sub.4, H.sub.2ax, H.sub.6ax,     3H); 3.05-3.75     (m, H.sub.2eg, H.sub.6eg, H.sub.7, 3H); 6.05 (s, H.sub.7", 2H); 6.28 (dd,     H.sub.6", 1H); 6.58     (d, H.sub.2", 1H); 6.65 (d, H.sub.5", 1H); 7.10-7.50 (m, H.sub.2',     H.sub.3', H.sub.5', H.sub.6', 4H).     paroxetine:     1H-NMR (ppm): 1.60-2.00 (m, H.sub.ax, H.sub.5eg, 2H); 2.00-2.35 (m,     H.sub.3, 1H);     2.40-2.95 (m, H.sub.4, H.sub.2ax, 3H); 3.15-3.70 (m, H.sub.2eg,     H.sub.6eg, H.sub.7, 2H);     5.67 (s, H.sub.7, 2H); 6.11 (dd, H.sub.6", 1H); 6.43 (d, H.sub.2", 1H);     6.62 (d, H.sub.5", 1H);     6.80-7.35 (m, H.sub.2', H.sub.3', H.sub.5', H.sub.6', 4H).     ______________________________________

It will be clear that the invention is not limited to the above description, but is rather determined by the following claims. 

We claim:
 1. A compound having the formula: ##STR11## wherein R² represents C₁ -C₁₀ alkyl group or a substituted or unsubstituted phenyl group wherein the substituents are selected from the group consisting of C₁ -C₁₀ alkyl, halogen, nitro, hydroxy, alkoxy, and combinations thereof.
 2. The compound according to claim 1, wherein the R² group represents a C₁ -C₄ alkyl group.
 3. The compound according to claim 1, wherein the R² group is a C₁ -C₂ alkyl group.
 4. The compound according to claim 1, having a solubility at about 20° C. of at least about 10 mg per ml water.
 5. The compound according to claim 4, having a solubility in water of at least 1000 mg per ml at about 20° C.
 6. A process, which comprises mixing together a compound, a salt, and/or a base thereof, having the formula: ##STR12## with a sulfonic acid of the general formula R² -SO₃ H, wherein R² represents C₁ -C₁₀ alkyl group or a substituted or unsubstituted phenyl group wherein the substituents are selected from the group consisting of C₁ -C₁₀ alkyl, halogen, nitro, hydroxy, alkoxy, and combinations thereof,to produce a sulfonate salt compound according to claim
 1. 7. The process according to claim 6, which further comprises mixing together said sulfonate salt compound with a reagent selected from the group consisting of hydrochloric acid, hydrobromic acid, hydriodic acid, acetic acid, propionic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, citric acid, embonic acid/pamoic acid, sulfuric acid, water, methanol, and ethanol, to form a salt or solvate of said reagent.
 8. The process according to claim 7, wherein the salt of said reagent is produced and is recovered as a solid having a purity of at least 90 wt %.
 9. The process according to claim 7, wherein said reagent is maleic acid; said mixing produces paroxetine maleate; and which further comprises recovering said paroxetine maleate in a purity of at least 98%.
 10. The process according to claim 7, wherein said reagent is acetic acid; said mixing produces paroxetine acetate; and which further comprises recovering said paroxetine acetate in a purity of at least 98%.
 11. A process according to claim 6, which further comprises mixing together said sulfonate salt compound with at least one of an organic or an inorganic base to form a free base thereof.
 12. The process according to claim 11, wherein the base is selected from the group consisting essentially of: sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, triethylamine, and pyridine.
 13. The process according to claim 11, further comprising isolating said free base in a purity of at least 95%.
 14. The process according to claim 13, wherein said isolated free base has a purity of at least 98%.
 15. The compound produced by the process according to claim
 6. 16. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and at least one pharmaceutically acceptable carrier or diluent.
 17. The pharmaceutical composition according to claim 16, wherein said composition is a solid dosage form.
 18. A method for treating depression, obsessive/compulsive disorders, panic disorders, bulimia, anorexia, pain, obesity, senile dementia, migraine, or social phobias, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound as claimed in claim
 1. 19. The method according to claim 18, wherein said patient is a human.
 20. The method according to claim 18, wherein said method comprises administering an effective antidepressant amount of said compound to a patient suffering from depression.
 21. A compound of the following formula: ##STR13##
 22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the following formula: ##STR14## wherein R² is methyl, ethyl, benzyl, p-chlorobenzyl, or tolyl; and a pharmaceutically acceptable carrier or diluent.
 23. The pharmaceutical composition according to claim 22, wherein said composition is for oral administration.
 24. The pharmaceutical composition according to claim 22, wherein R² is methyl.
 25. The pharmaceutical composition according to claim 24, wherein said composition is a solid dosage form.
 26. The pharmaceutical composition according to claim 25, wherein said composition is a tablet.
 27. A method of treating depression, obsessive/compulsive disorders or panic disorders which comprises administering to a patient in need thereof an effective amount of a compound of the following formula: ##STR15## wherein R² is methyl, ethyl, benzyl, p-chlorobenzyl, or tolyl.
 28. The method according to claim 27, wherein R² is methyl.
 29. The method according to claim 28, wherein an effective antidepressant amount is administered to said patient. 